Pembrolizumab induced high rates of durable responses in advanced melanoma

Issue: June 25, 2014

CHICAGO — A majority of patients with advanced melanoma who had and had not received previous ipilimumab demonstrated durable responses with the PD-1 targeted antibody pembrolizumab, according to study results presented at the ASCO Annual Meeting.

Perspective from Steven O'Day, MD

“This is the largest phase 1 clinical trial ever conducted in this disease, and together with a lung cancer cohort, this is the largest phase 1 trial ever done in oncology,” study investigator Antoni Ribas, MD, PhD, professor of medicine at the David Geffen School of Medicine at the University of California in Los Angeles, said during a press conference. “These are early data, but they tell us we are on to something really important.”

Antoni Ribas

Ribas and colleagues sought to evaluate pembrolizumab (Merck) — formerly known as lambrolizumab and MK-3475, and which received a priority review designation from the FDA in May — in 411 patients with advanced melanoma. Of these patients, 221 had previously received ipilimumab (Yervoy, Bristol-Myers Squibb), and 190 had not.

The trial included three dosing schedules: 2 mg/kg every 3 weeks (n=162); 10 mg/kg every 3 weeks (n=192); and 10 mg/kg every 2 weeks (n=57).

The analysis occurred after all patients had at least 6 months of follow-up; 75% of patients had at least 9 months of follow-up.

Of the 356 patients with measurable disease at baseline, 40% (95% CI, 32-48) of patients who had received previous ipilimumab and 28% (95% CI, 22-35) who had not responded to treatment with pembrolizumab. The overall response rate was 34% (95% CI, 29-39).

Median PFS among ipilimumab-naive patients from all dosing schedules was 24 weeks (95% CI, 16-48), and 51% of these patients achieved 24-week PFS.

Median PFS among the cohort previously treated with ipilimumab was 23 weeks (95% CI, 14-24), and 44% of these patients achieved 24-week PFS.

Eighty-eight percent of responses were ongoing at the time of the analysis, and the median response duration was not reached (range, 6+ weeks to 76+ weeks).

Researchers observed responses among patients from all dosing schedules, regardless of ECOG performance status, lactate dehydrogenase levels, BRAF mutation status, tumor stage and prior therapies.

Median OS had not been reached at the time of the analysis. The estimated 1-year OS rate was 69% for all patients, 74% for those without previous ipilimumab and 65% for those who had received ipilimumab.

“Not too long ago, we used to say that median OS for these patients was 6 to 9 months, and then it was getting closer to 12 months,” Ribas said. “Here we have not reached the median OS. At the most recent follow-up survival rates seem to be plateauing, and this is obviously something we will have to follow longer.”

Grade 3 to grade 4 adverse events occurred in 12% of patients, and 4% discontinued due to an adverse event. The most common toxicities of any grade were fatigue (36%), pruritus (24%) and rash (20%). No patients died due to a drug-related toxicity.

For more information:

Ribas A. Abstract #LBA9000. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Disclosure: The study was funded by Merck. Researchers report consultant/advisory roles or employment/leadership positions with; research funding, honoraria or other remuneration from; and stock ownership in, Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Kite Pharma, MedImmune, Merck, Novartis, Oncoscience and Roche.

Perspective

Steven O'Day, MD

This is the second PD-1 antibody. The data is remarkably similar with this approach and nivolumab (BMS-936558, Bristol-Myers Squibb).

This is just blocking one checkpoint, and yet in melanoma, about two-thirds of patients appear to be getting some clinical benefit, either with stable disease or tumor shrinkage. And there’s objective tumor responses in almost 40% of patients in this series.

The other important point, prior exposure to ipilimumab doesn’t seem to have any dramatic effect, and this is critical to us understanding combining and sequencing these drugs. There doesn’t appear to be a lot of cross resistance. The combination may be even better, but sequences are also potentially very helpful.

What’s really remarkable is that almost 90% of these patients are having durable responses, with a toxicity profile that is almost unheard of in metastatic cancer. This is really extraordinary about this class of drugs.

Steven O'Day, MD

Clinical associate professor of medicine

University of Southern California

Keck School of Medicine

Disclosures: